2-{8 3,5-Disubstituted-4H-1,2,4-triazol-4-yl{9 benzhydrol

ABSTRACT

Compounds of the formula VI   tr wherein R and R1 are hydrogen, methyl or ethyl, or together   is piperidino, pyrrolidino or morpholino; wherein R2 is hydrogen, chlorine or fluorine; and wherein R3 is hydrogen or fluorine, are prepared by reducing a 2-(3,5-disubstituted-4H1,2,4-triazol-4-yl) benzophenone to obtain the corresponding 2(3,5-disubstituted-4H-1,2,4-triazol-4-yl)benzhydrol or by reducing with borane a 4-(2-benzoylphenyl)-5-Substituted-4H1,2,4-triazole-3-carboxaldehyde 3-(0-acyloxime) (obtained by acylating the corresponding oxime to give the corresponding 2-(3(aminomethyl)-5-substituted-4H-1,2,4-triazol-4-yl)benzhydrol. The novel compounds of formula VI and the pharmacologically acceptable acid addition salts thereof are active sedatives.

United States Patent 1 Gall et al.

[ *Oct. 7, 1975 1 2-[3,5-DlSUBSTlTUTED-4H-l,2,4-TRlAZOL- 4-YL1BENZHYDROL [75] Inventors: Martin Gall, Kalamazoo; Jackson B.

Hester, Jr., Galesburg, both of Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

[ Notice: The portion of the term of this patent subsequent to May 28, 1991, has been disclaimed.

[22} Filed: Oct. 29, 1973 211 Appl, No; 410,781

Related US. Application Data [63} Continuation-impart of Ser. No. 172,919, Aug. 18,

[52] US. Cl 260/308 R; 71/92; 260/2471 E; 260/2475 E, 260/268 MK; 260/293.69;

[51] lnt. Cl. C07D 249/08; C07D 401/06; C071) 403/06; C07D 413/06 [58] Field of Search... 260/308 R, 247.5 E, 293.69

[56] References Cited UNITED STATES PATENTS 3,813,412 5/1974 Gall et a1. 260/308 R Primary ExaminerAlton D. Rollins Attorney, Agent, or Firm-Hans L. Berneis [57] ABSTRACT Compounds of the formula V1 wherein R and R, are hydrogen, methyl or ethyl, or together The novel compounds of formula V1 and the pharmacologically acceptable acid addition salts thereof are active sedatives.

4 Claims, No Drawings 2-[ 3 ,5-DlSUBSTITUTED-4H-l ,2,4-TRIAZOL-4- YL BENZHYDROL CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of application Ser. No. l72,9l9, filed Aug. l8, l97l, now US. Pat. No. 3,813,4l2v

BRIEF SUMMARY OF THE INVENTION FIELD OF THE INVENTION 7 lustratively represented in Schemes A and B as follows:

Scheme A CHZ'NI CH=N-OAc R3 R2 IV N cH CH2'NH2 OH (:1

H V R3 R2 IR CH -N H \Rl H R R3 2 The compounds of formula VI are a combination of formula II and V, and are encompassed by this invention.

In the above formula (I through VI), R,, and R,,' are methyl, ethyl, or

is piperidino, pyrrolidino or morpholino; R and R are hydrogen. methyl or ethyl, or together is piperidino, pyrrolidino, or morpholino; R is hydrogen, fluorine 0r chlorine; and R is hydrogen or fluorine.

The most desirable products of this invention have the formula VII CH N CHZ-N/ Vll wherein R and R, is hydrogen or methyl, or together is pyrrolidino; wherein R is hydrogen or chlorine and the pharmacologically acceptable acid addition salts thereof. The pharmacologically acceptable acid addition salts of the compounds of formula VI are also encompassed by this invention.

The process of Method A comprises reducing a compound of formula I wherein R R',,, R and R are defined as hereinabove. with an alkali metal borohydride, e.g. sodium or potassium borohydride or lithium tri- (tertbutoxy) aluminum hydride.

The process of Method B comprises acylating a compound of structure Ill to produce IV with an acid anhydride of an alkanoic acid of 2 to 3 carbon atoms, inclusive, followed by a simultaneous reduction of the carbonyl group and the oxime O-ester of IV with borane to give the compound of formula V. Pharmacologically acceptable acid addition salts are produced by reacting compounds of formula VI (II or V) with an excess of the selected acid.

DESCRIPTION OF THE PREFERRED EMBODIMENT The compounds of formula VI have sedative, tranquilizing, and hypnotic effects.

Sedative effects of 5-chloro-2[3-aminomethyl)-5- methyl-4H-l,2,4-triazol-4-yl]benzhydrol are shown by the following tests in mice:

Chimney test: [Med Exp. 4, I45 (l962)]: The effective intraperitoneal dosage for 50% of mice (ED is 4.5 mg./kg. The test determines the ability of mice to back up and out of a vertical glass cylinder within 30 seconds. At the effective dosage, 50% of the mice failed doing it.

Dish test: Mice in Petri dishes l cm. diameter, 5 cm. high, partially embedded in wood shavings), climb out in u very short time, when not treated. The mice remaining in the dish for more than 3 minutes indicates tranquilization. The ED equals the dose of the test compound at which 50% of the mice remain in the dish. The ED (intraperitoneal administration) in this test was 2.8 mg./kg.

Pedestal test: The untreated mouse leaves the pedestal in less than a minute to climb back to the floor of the standard mouse box. Tranquilized mice will stay on The following compounds have (by intraperitoneal injection) EDS" values as shown in the table below:

ED (in mg./kg.)

P Ni

COMPOUND CH D 2[ 5-methyl-3-( pyrrolidinomethyl 4H-l ,2,4-triazol 4'yl lbenzhydrol (A) 28 3.5 5.0 2.5 2[ 5mcthyl-3-( pyrrolidinomcthyl J 4H- 1 ,lA-triazol-4-yl jhenzhydrol (B) l l I4 16 I41] Ch Chimney test D dish test P pedestal test Ni nicotine antagonism (3) test The pharmaceutical forms contemplated by this invention include pharmaceutical compositions suited for oral, parenteral and rectal use, e.g., tablets, powder packets, caehets, dragees, capsules, solutions, suspensions, sterile injectable forms, suppositories, bougies, and the like. Suitable diluents or carriers such as carbohydrates (lactose), proteins, lipids, calcium phosphate, cornstarch, stearic acid, methylcellulose and the like may be used as carriers, or for coating purposes. Oil, e.g., coconut oil, sesame oil, safflower oil, cottonseed oil, peanut oil, may be used for preparing solutions or suspensions of the active drug. Sweetening, coloring, and flavoring agents may be added.

For mammals and birds food premixes, with starch, oatmeal, dried fishmeat, fishmeal, flour and the like can be prepared.

As tranquilizers the compounds of formula VI can be used in dosages of 05-20 mg./kg. in oral or injectablcpreparations as described above, to alleviate tenrl and anxiety in mammals, or birds, such as e.g., occ; when animals are in travel.

The pharmacologically acceptable acid addition salts of compounds of formula VI contemplated in this invention, are the hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, cyclohexanesulfamates. methanesulfonates, and the like, prepared by reacting a compound of formula VI with the selected pharmacologically acceptable acid.

As feed additives the compounds of formula VI can be used in dosages of 0.3 mg. to 50 g. per ton of feed to increase growth, feed consumption, and feed effici enty in livestock and poultry, milk production in the mammalian species and egg production in the avian species.

Other acid addition salts of the compounds of formula IV can be made such as the fluosilicic acid addition salts which are useful mothproofing compounds, or the trichloroacetates useful as herbicides against Johnson grass, Bermuda grass, yellow foxtail and green foxtail, and quack grass.

The starting materials, compounds of formula I, are produced as shown in the preparations and as earlier disclosed in application Ser. No. l l4,049, filed Feb. 9, 1971, by Jackson B. Hester, Jr., now U.S. Pat. No. 3,7- 09,898. The starting compounds of formula III are also disclosed in the preparations and in the above cited patent application.

In carrying out the process of this invention by MEthod A a selected 2-[3-substituted 4H-l,2,4- triazo]-4-yl)benzophenone l is treated with a reducing agent, e.g. an alkali borohydride such as sodium or potassium borohydride or lithium tri-(tert.-butoxy) aluminum hydride in an organic solvent. As solvents, lower-alkanols (with the borohydrides only) and ethers e.g. methanol, ethanol, land Z-propanol, ethyl ether, dibutyl ether tetrahydrofuran and the like can be used. In the preferred embodiment of this invention, compound I is stirred between 6 to 36 hours with the reductant in the selected solvent, in a nitrogen atmosphere, at first at low temperature between 5 and 10 C. till all the solid is added, then at room temperature (2225 C.). However, temperatures up to 50 C. are operative. At the termination of the reaction, the products (II) are recovered and purified by conventional means such as extraction, chromatography, crystallization and the like. Two different diastereomers are generally isolated by chromatography.

In Method B a selected 4-( 2-benzoylphcnyl)-4H- l,2,4-triazolc-3-carboxaldehyde 3-oxime III is acylated with a lower alkanoic acid anhydride in a conventional manner e.g. with acetic or propionic anhydride, preferably in an organic solvent, e.g., pyridine, benzene, or tetrahydrofuran, in a nitrogen atmosphere, at temperatures between 0-4() C. The product IV, an O- acyloxime, is recovered and purified by convenional procedures: pouring the reaction mixture into water and recovering a crude product by filtration or extraction, which can be purified by crystallization.

Compound IV is converted to the corresponding 2- [3-( aminomethyl )-4H- l ,2,4-triazol-4-yl )lbenzhydrol (V) by treating IV with a solution of borane (EH in a solvent e.g. ether, tetrahydrofuran, methanol, ethanol, and the like. In the preferred embodiment of this invention, the borane is used in excess, in a nitrogen atmosphere, with tetrahydrofuran as solvent during 2-36 hours. The reaction is carried out at first at low temperatures for l-4 hours and then continued for the remainder of time at between 40 C. generally at room temperatures, 2226 C. At the termination of the reaction the reaction mixture is treated under cooling with hydrochloric acid and the product recovered and purified by conventional means. eg filtrations, extractions, chromatography, crystallization, and the like.

The following examples are illustrative of the processes and products of the present invention, but are not to be construed as limiting.

PREPARATION l 2'-Benzoly-4-chloroacetanilide Acetyl chloride (8L3 g., l.037 mole) was added to a stirred solution of 2'amino-5-chlorobenzophenone (200.0 g., 0.864 mole) and pyridine (68.4 g., 0.864 mole) in ether (4. l the mixture was kept at ambient temperatures for 2 hours and treated with 500 ml. of water. The layers were separated and the ether layer was dried over anhydrous sodium sulfate and concentrated. Crystallization of the residue from ethyl acetate- Skellysolve B hexanes gave: 124.0 g. of 2'-benzoyl-4- chloroacetanilide of melting point ll4l [5 C. Two more crops of 2'-benzoyl'4'-chloroacetanilide also were obtained: 67.8 g. of melting point I l3.5l l4.5 C. and 33.0 g. of melting point 1 l3l 14 C.

PREPARATION 2 6-Chloro-4-phenyl-2( lH )-quinolone The procedure (reaction of 2-benzoyl-4- chloroacetanilide with sodium hydroxide) of A. E. Drukker and C. I. Judd, J., Heterocyclic Chem. 3, 359 (2966) was used for this preparation. The yield was 77 percent. Two other preparations have been described: S. C. Bell, T. S. Sulkowski, C. Gochman and S. J. Chil dress, J. Org. Chem. 27,562 (1962); G. A. Reynolds and C. R. Hauser, J. Amer. Chem. Soc. 72, l852 (1950).

PREPARATION 3 2,6-Dichloro4-phenylquinoline The procedure of A. E. Drukker and C. I. Judd, J. Heterocyclic Chem. 3,359 (I966) was used for this preparation. The yield was 62 percent.

PREPARATION 4 6Chloro-2-hydrazino4-phenylquinoline A stirred mixture of 2,6-dichloro-4-phenylquinolinc (2.7 g., 0.01 mole) and hydrazine hydrate (6.8 g.) was refluxed under nitrogen for 1 hour and concentrated in vacuo. The residue was suspended in warm water, and the solid was collected by filtration, dried and recrystallized from ethyl acetate-Skelly B hexanes to give l.8l g. (67% yield) of 6-chloro-2-hydrazino-4- phenylquinoline of melting point l56.5l 57 C.

Anal. Calcd. for C H, ClN;,: C, 66.79; H, 4.49; CI, l3.l5; N, i558. Found: C, 67.15; H, 4.65; CI, l3.l9; N, 15.32.

PREPARATION 5 7 -Chlorol -methyl-5-phenyl-s-triazolo- 4,3-a]quinoline A stirred mixture of 6-chloro-l-hydrazino-4- phenylquinoline (1.4 g., 0.0052 mole), triethyl orthoacetate (0.925 g., 0.0057 mole) and xylene ml.) was refluxed, under nitrogen, for 2 hours 40 minutes. During this period the ethanol formed in the reaction was removed by distillation through a short, glass helixpacked column. The mixture was concentrated to dryness in vacuo and the residue was crystallized from methanol-ethyl acetate to give: L02 g. of 7-chloro-l methyl-5-phenyl-s-triazolo-[4,3-alquinoline of melting point 253.5255 C. and 0.26 g. of melting point 253.5255 C. (83.9 percent yield). The analytical sample was crystallized from methylene chloride:methanol and had a melting 'point 252.5253.5 C.

Anal. calcd. for C H CIN C, 69.50; H, 4.l2, Cl, 12.07; N, 14.31. Found: C, 69.39; H,4.02; Cl, 12.10, N, l4.49.

PREPARATION 6 -Chloro-2-( 3-methy1-4H- l ,2,4-triazol-4 ylJbenzophenone (Oxidation of 7-chlorol -methyl-5-phenyl-s-triazolo[ 4,3 alquinoline) A stirred suspension of 7-ch1oro-l-methyl-S-phenyls-triazolol4,3-alquinoline (2.94 g., 0.01 mole) in acetone (1 ml.) was cooled in an ice-bath and treated slowly with a solution prepared by adding sodium peri odate (2 g.) to a stirred suspension of ruthenium dioxide (200 mg.) in water (35 ml.). The mixture became dark. Additional sodium periodate (8 g.) was added during the next minutes. The ice bath was removed and the mixture was stirred for 45 minutes. Additional sodium periodate (4 g. was added and the mixture was stirred at ambient temperature for 18 hours and filtered. The solid was washed with acetone and the combined filtrate was concentrated in vacuo. The residue was suspended in water and extracted with methylene chloride. The extract was dried over anhydrous potassium carbonate and concentrated. The residue was chromatographed on silica gel (100 g.) with 10% of methanol-90% ethyl acetate; 50 ml. fractions were col lected. The product was eluted in fractions 10-20 and was crystallized from ethyl acetate to give: 0.405 g. of melting point 168l69.5 C. and 0.291 g. of melting point l67.5l69 (23.4% yield) of 5ch1oro-2-( 3- methyl4H-l .2,4-triazol-4-yl)benzophenone. The analytical sample had a melting point of 168 C.

Anal. calcd. for C H CIN O: C, 64.54; H. 4.06; C1, 11.91; N, 14.11. Found: C, 64.56; H, 4.35; CI, 11.97; 11.93; N, 14.29

PREPARATION 7 Oxidation of 7-ch1oro-1-methyl-5-phenyl-s-triazolo[4,3-a]quinoline A stirred suspension of 7-chloro-l-methyl-S-phenyls-triazolo[4,3-alquinoline (2.94 g.. 0.01 mole) and acetone (200 ml. was cooled in an ice bath and treated, dropwise. during 15 minutes with a solution prepared from ruthenium dioxide (200 mg), sodium periodate (4g. and water (35 ml. A slight exothermic reaction Was noted and the mixture became dark. After 10 min utes. 29 ml. of a solution of sodium periodate (12 g.) in water (70 ml.) was added during 10 minutes. This mixture was stirred for 2 hours and then the remaining sodium periodate solution (41 ml.) was added during the next 3 hours. The mixture was concentrated in vacuo to remove acetone. The resulting aqueous mixture was extracted with methylene chloride. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was chromatographed on silica gel (150 g.) with 2% me thanol-987( chloroform; 60 ml. fractions were collected. Recovered starting material was eluted in fractions 1 ll4 and crystallized from methanol-methylene chloride to give 0.069 g. ofmelting point l .5253.5 C. A mixture of the two products was eluted in frac' tions 1539. Crystallization of this mixture from ethyl acetate gave 618 mg. (20.8%) of 5-chloro-2-( 3-methy1- 4H-l 2.4-triazo1-4-yl)benzophenone of melting point l65.5l68. Crystallization of the mother liquor from methanol gave 0.126 g., melting point l08l 12 and 0.588 g. of melting point l0l.5105.5 (decomposition) 19.9 percent yield) of a methanol solvate of 4-( 2- benzoyl-4-chlorophenyl)-5 methyl-4H 1 .2.4-triazole- 3-carboxaldehyde. The analytical sample had a melting point l00l0l.5 C.

Anal. calcd. for C H ClN O z C, 62.68; H, 3.71; Cl, 10.89; N, 12.90. Found: C, 59.37; H, 4.89; CI, 9.75; N, l 1.30.

MeOH 9.34%; H O, 0.40%. Corrected for MeOH and H 0. C, 61.90; H, 4.06; CI, 10.80; N. 12.52.

Heating the solvate in a desiccator at C at 1 5 mm. Hg for 72 hours gave pure 4-( 2-benzoyl-4- chlorophenyl)-5-methy1-4H-1,2,4-triazo1e-3- carboxaldehyde.

PREPARATION 8 Oxidation of 7-chlorol methy1-5-phenyl-s-triazolo[ 4,3-alquinoline A vigorous stream of ozone in oxygen was bubbled for 12 hours, into a stirred, ice-cold solution of 7- chloro-1-methy1-S-phenyl-s-triazolo[4,3-a1quino1ine (31.1 g, 0.106 mole) in methanol (750 ml.) and methylene chloride (500 ml.). The resulting mixture was filtered and the filtrate was added to an ice-cold solution of sodium iodide (47.5 g.) and acetic acid (63 ml.) in water (200 ml.). The solution was decolorized by the addition of sodium thiosulfate and concentratd in vacuo. The residue was mixed with water and extracted with methylene chloride. The extract was washed (H O), dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (1.5 kg); 175 m1. fractions were collected. Fractions 1]28 were elutedwith 1% methanol-99% chloroform and fractions 129-168 with 5% methanol- 7( chloroform. The first compound was eluted in fractions 4960 and crystallized from methanol-ethyl acetate to give: 0.769 g. of melting point 229.5 23lC. (decomposition) and 0.535 g. of melting point 228C. (decomposition) of 7-chloro-l-methyl-5- phenyl-s-triazolo[4,3-a]quinolin-4(5H)-one. The analytical sample had a melting point 232233 C.

Anal. calcd. for C, H, C1N -,O: C, 65.92; H, 3.91; Cl, 11.44; N, 13.57 Found: C, 65.46; H. 3.72; CI, 11.48; N, 13.59

Recovered starting material was eluted in fractions 66-78 and crystallized from methylene chloride methanol to give 0.737 g. of melting point 25 l253.5 C. A mixture of the two remaining products was eluted in fractions 73-168. Crystallization of this mixture from ethyl acetate gave: 10.8 g. of melting point l16.5l67.5 C., 0.987 g. of melting point 116167 C. and 2.52 g. of melting point l64l65.5 C. (45.3 percent yield) of 5-chloro-2-(3-methyl-4H-l,2,4- triazol-4-yl)benzophenone. Crystallization of the mother liquor from methanol gave 5.62 g. of melting point 140141.5 C., 1.23 g. of melting point l00.5l02.5 (decomposition) and 1.04 g. of melting point l37.5 (20.8 percent yield) of 4-(2- benzoyl-4-chloro-phenyl)-5-methyl-4H-1 ,2,4-triazo1e- 3-carboxaldehyde.

PREPARATION 9 5-chloro-2-( 3-methyl- 4H- 1 .2,4triazol-4-y1)-benzophenone A stirred solution of silver nitrate (0.357 g., 0.0021 mole) in water (1.8 ml.) was treated with 1N sodium hydroxide (4. 1 ml. To the resulting stirred suspension of silver oxide was added a warm solution of 4 (2- benzoy1-4-chlorophenyl )-5-methyl-4H-l ,2,4-triazole' 3-carhoxaldehyde methanol solvate (326 mg.) in methanol (15 ml.). and the resulting mixture was stirred under nitrogen at ambient temperature for 18 hours. The solid was collected by filtration and washed with water and methanol. The filtrate was concentrated in vacuo to remove methanol and the resulting aqueous solution was cooled in an ice bath. neutralized with hydrochloric acid and extracted with chloroform. The residue was crystallized from ethyl acetate to give 0.l62 g. of 5-chloro-2-(3-methyl-4H-l,2,4-triazol-4- ylJ-henzophenone of melting point l69.5l7 1 C.

PREPARATION l 4-( 2- Benzoyl-4-ehlorophenyl )--methyl-4H- l ,2.4-

triazole-3-earhoxaldehyde 3-oxime A stirred mixture of 4-( 2-henzoyl-4-chlorophenyl )-5- methyl-4H- l ,ZA-triazolc- 3-earhoxaldehyde 3.26 g. hydroxylamine hydrochloride (0.765 g, 0.011 mole), sodium acetate (0.903 g.. 0.0ll mole) ethanol (50 ml.) and water 12.5 ml.) was refluxed, under nitrogen for 4.5 hours. (The product precipitated from the initially clear solution during the reflux period.) The cooled mixture was poured into cold water, and the solid was collected by filtration, washed with water and PREPARATION I l 6-chloro-4-( lo-difl uorophcnyl )-2-hydrazinoquinoline In the manner given in Preparation 4, 2,6-dichloro-4- ilo-difluorophenyl )quinoline (prepared as in Preparations l to 3) was reacted at reflux with hydrazine hydrate to give 6-chloro-4- (2 6-difluorophenyl)-2- hydrazinoquinoline.

PREPARATION l2 7-chloro- I -methyl-5-( 2.6-difluorophenyl )-striazolo[4.3-a]quinoline In the manner given in Preparation 5, 6-chloro-4- (lo-difl uorophenyl )-2-hydrazinoquinoli ne and triethyl orthoaeetate are refluxed in xylene to give 7-chloro-I- methyI-5-( 2,6-difluorophenyl )-s-triazolo[4,3- alquinoline.

PREPARATION l3 In the manner given in Preparation 6, 7-chloro-lmethyl-5-( lo-difluorophenyl )-s-triazolo[4,3- a]quinoline was oxidized at low temperature with sodium periodate and ruthenium dioxide to give 5 chloro-Z'.6'-difluoro-2-( 3-methyl-4H- l .2.4-triazol-4- yl )henzophenone.

PREPARATION I4 6-chloro-4-(o-chlorophenyl )-2-hydrazinoquinoline In the manner given in Preparation 4. 2.6-dichloro-4- (o-chlorophenyl)-quinoline (prepared as in Preparations l to 3) was reacted at reflux with hydrazine hydrate A to give 6-chloro-4-(o-chlorophenyl)-2- hydrazinoquinoline.

PREPARATION I S 7-chloro- I -methyl-5 o-chlorophenyl )-s-triazolo[4,3- a]quinoline In the manner given in Preparation 5, 6-chloro-4(o chlorophenyl)2-hydrazinoquinoline and triethyl orthoacetate were refluxed in xylene to give 7-chloro-l methyl-S-(o-chlorophenyl )-s-triazolo[4,3-ajquinoline.

PREPARATION l6 2,5-Dichloro-2-( 3-methyl-4H- I 2.4-triazol-4- yl )henzophenone In the manner given in Preparation 6, 7-chloro-lmethyl-5-( o chlorophenyl )-s-triazolo[4.3-a ]quinoline was oxidized at low temperature with sodium periodatc in the presence of ruthenium dioxide to give 2, 5- dichloro-2-( 3-methyl-4H- I ,2.4-triazol-4- yl )henzophenone.

PREPARATION l7 4[ 2-( o'chlorohenzoyl )-4-chlorophenyl 1-5 -methyI-4 H- l,2,4-triazole-3-carhoxaldehyde In the manner given in Preparation 7. 7-chlom lmethyl-5-(o-chlorophenyl )-s-triazo]o[4,3-a1quinoline was oxidized with ruthenium dioxide and sodium periodate I in acetone solution to give 4-[2-(0- chlorohenzoyl )-4-chlorophenyl l-5-methyl-4H- l ,2,4 triazole-3-carhoxaldehyde PREPARATION l8 4[ 2-( o ehlorohenzoyl )-4-chlorophenyl ]-5 -methyI-4H- l,l4-triazole-3-carhoxaldehyde 3-oxime In the manner given in Preparation l0. 4-[2-(ochlorohenzoyl )-4-chlorophenyl ]-5-methyl 4H- l ,2,4- triazolo-3-carhoxaldehyde was heated with hydroxylamine hydrochloride and sodium acetate in aqueous ethanol (\/V) to give 4[2-(o-chlorobenzoyI-4- chlorophenyl ]5 methyl-4H4 ,2,4-triazolc-3- carhoxaldchyde 3oxime.

PREPARATION l9 4-[ 2-( lfi-difluorobcnzoyl )-4-chlorophenyl ]-5-methyl- 4H- I .2,4-triazole-3-carhoxaldehyde In the manner given in Preparation 7, 7-chlor0-I- methyl-5-( 2.6-difluorophenyl )-s-triazolo[ 4,3- a]quinolinc was oxidized with ruthenium dioxide and sodium periodate in acetone solution to give 4[ 2-( 2,6- difluorobenzoyl )-4-chlor0phenyl]-5-methyl-4H- l 2,4- triazolo-3-carhoxaldehyde.

PREPARATION 2a 4-{ 2-(2,6-difluorobenzoyl)-4-ehlorophenyl1-5-methyl- 4H- l .ZA-triazole- 3-carhoxaldehyde 3-oxime.

In the manner given in Preparation l0, 4-[2-(2,6 difluorobenzoyl )-4-chlorophenyl ]-5-methyl-4H- l 2.4- triazole-3-carboxaldehyde was heated with hydroxylamine hydrochloride and sodium acetate in 80% aqueous ethanol (V/V) to give 4-[2-( 2,6-difluorobenzoyl-4- chlorophenyll--methyl-4l-l-1,2,4-triazo1e-3- carboxaldehyde 3-oxime.

PREPARATION 21 5-chloro-2-l3-(hydroxymethyl)-S-methy1-4l-ll ,2,4- triazol-4-y1 ]benzophenone A stirred mixture of 5-ch1oro-2-(3-mcthyl-4H-1,2.4- triazolo-4-yl )benzophenone, (2.98 g., 0.01 mole) paraformaldehyde (3 g.) and xylene 100 ml.) was warmed under nitrogen, in a bath maintained at 125 C. for 7 hours. The mixture was then concentrated in vacuo. The residue was chromatographed on silica gel 150 g.) with 3% methanol-977: chloroform. Fifty-ml. fractions were collected. The product was eluted in fractions -44. The fractions were concentrated and the residue was crystallized from ethanol-ethyl acetate to give: 1.64 g. of melting point 138l42 C.; 0.316 g. of melting point 138.5l4l C.; 0.431 g. of melting point 139141 C. (72.8% yield) of 5-ch1oro-2-[3- (hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4- yl]benzophenone. The analytical sample had a melting point of 138l 39 C.

Anal. calcd. for C, H ClN;,O C, 62.30; H, 4.30; C1, 10.81; N, 12.82. Found: C, 62.23; H, 4.22; Cl, 10.82; N, 1 1.73.

PREPARATlON 22 5-chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4- triazol-4-yl]benzophenone A solution of 5-chloro-2-[3-(hydroxymethyl)-5- methy1-4H- l ,2,4-triazo1-4-yl lbenzophenone (328 mg.. 0.001 mole) in dry, hydrocarbon-stabilized chloroform (5 ml. was cooled in an ice bath and treated with phosphorus tribromide (0.1 ml. The colorless solution was kept in the ice bath for 55 minutes, at ambient temperature (22-24 C.) for 5 hours. The resulting yellow solution was poured into a mixture of ice and dilute sodium bicarbonate. This mixture was extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized from methylene ehloridcethyl acetate to give: 0.285 g. of melting point 200240 (decomposition) and 0.030 g. of melting point 200-220 (decomposition) of 5-chloro-2-[3- (bromomethyl )-5-methyl-4H- 1 ,2,4-triazo1-4- yl]benzophenone. The analytical sample had a melting point of 200-240 C.

Anal. calcd. for C H Br C1N,,O; C, 52.26; H, 3,35; Br, 20.46; Cl, 9.08; N, 10.76 Found: C, 52.13, 52.45; H, 3.77, 3.66; Br, 20.44; Cl, 9.20; N. 10.43

PREPARATION 23 5-ch1oro-2-[ 3-(dimethylamino )methyl J-S-methyl-4H- 1 .2,4-triazol-4-y1)benzophenone A stirred suspension of 5-chloro-2-[ 3- (bromomethylJ-S-methy1-4H-1.2,4triazo1-4- yllbenzophenone in tetrahydrofuran was cooled in an ice-bath and treated with dimethyl amine in methanol. The resulting solution was allowed to warm to ambient temperature and stand for 24 hours. It was then concentrated in vacuo. The residue was suspended in water, treated with a little sodium bicarbonate, and extracted with methylene chloride. The extract was washed with brine, dried with anhydrous potassium CH2-N wherein R, R,, R and R have the significance of hereinabove, are produced.

PREPARATION 24 5-eh1oro-2-[3-[(methylamino)methyl1-5-methyl-4H- 1 ,2,4-triazol-4-yl benzophenone Prepared in a nitrogen atmosphere form 2-[3- (hromomethyl )-5-methyl-4H- l ,2,4-triazo1-4- yl ]benzophenone in methanol and tetrahydrofuran and monomethylamine, had a melting point of 174l75 C.

5-chloro-2-[ 3-[pyrrolidinomethyl l-5-methyl-4H- l,2,4-triazol-4-y1lbenzophenone was made in similar manner with pyrrolidine and had a melting point of 168 to 171 C.

5-ch1oro-2-[ 3 diethylamino )methyl ]-S-methy1-4H- 1,2,4-triazol-4-y1]benzophenone had a melting point of 1 10.51l1.5 C.

5-chloro-2-[ 3-( piperidino )methyl )-5-methy1-4H- l,2,4-triazo1-4-yllbenzophenone was isolated as an oil. lts hydrochloride salt had a melting point of 226-242 (decomp).

PREPARATION 25 5-ch1oro-2-[ 5-'methyl-3-( morpholinomethyl)-4H- l .2,4-triazol-4-y1lbenzophenone A mixture 011' 3.0 m1. of 37% formalin (1.1 g., 37 mmol) 1.31 g. of morpholine (15.0 mmol) and 7.5 m1. of 2N HCl dissolved in 10 mg. of diglyme was placed in a ml. flask with magnetic stirrer bar and reflux condenser. The solid 5-ehloro-2-[3methyl-4H-1,2,4- triazo1-4-yl1-benzophenonc 1.488 g., 4.00 mmol) was added in one portion. and the solution was refluxed for 24 hours. It was worked up by quenching in 5% aqueous sodium hydroxide (ph 9) and extracting with benzene. Attempts to crystallize the dried product failed and the material was chromatographed on Silica Gel (200 g.) using varying amounts of methanol in chloroform as eluent (i.e. l liter of chloroform, l liter of 1% methanol chloroform and 1 liter of 5% methanol chloroform). One hundred and fifty ml. fractions were collected. Fractions and 21 contained the pure product. Fraction 22 contained primarily the product contaminated with an unknown material oflower Rf. Trituration of fractions 20 and 21 in ether separated the product from a gummy residue to give, after removal (under vacuum) of ether: 500 mg. of solid 5-chloro-2- [3-methyl-5-(morpholinomethyl)-4H-1,2,4-triazol-4- yl]-benzophenone of melting point l28l30 C. Recrystallization yielded 350 mg. of large prisms of melting point l28.5-l 30.5 C.

Anal. calcd. for C H ClN O C, 63.56; H, 5.34; N, l4.l2; Cl, 8.93. Found: C, 63.4]; H, 5.37; N, 14.21; Cl, 9.08.

PREPARATION 26 2,5-dichloro-2-[ 3-( hydroxymethyl-S-methyl-4H- l ,2,4-triazol-4-yl lbenzophenone In the manner given in Preparation 2 l, 2',5-dichloro- 2( 3-methyl-4H- l ,2,4-triazole-4-yl)benzophenone was heated with paraformaldehyde in xylene to give 2,5- dichloro-2-{3-(hydroxymethyl)-5-methyl-4H-1,2,4- triazol-4-yl lhcnzophenone.

PREPARATION 27 2,5-dichloro-2-[ 3-( hromomethyl )-5-methyl-4H- l ,2,4- triazol-4-yl ]henzophenone In the manner given in Preparation 22, 2',5-dichloro 2-[ 3-( hydroxymethyl )-5-methyl-4H- l ,2,4-triazol-4- yl ]benzophenone in chloroform was treated with phosphorus tribromide to give 2',5-dichloro-2-{3- (bromomethyl J-S-methyl-4H- l ,2,4-triazol-4- yl ]benzophenonc.

PREPARATION 28 2'5-dichloro-2 [3-[(dimethylamino)methyl1-5- methyl-4H- l ,2,4-triazol-4-yl lhenzophenone In the manner given in Preparation 23, 2'5'-dichloro- 2-[ 3-( hromomethyl )-5-methyl-4H- l ,2,4-triazol-4- yl]benzophenone in tetrahydrofuran was treated with dimethylamine to give 2',5-dichloro-2-[3- [(dimethylamino) methyl ]-5-methyl-4H- l ,2,4-triazol- 4-yl]benzophenone.

PREPARATION 29 2'6"difluoro-2-[ 3-( hydroxymethyl-5-methyl-4H- l ,2,4- triazol-4-yllbenzophenone In the manner given in Preparation 2i, 2'6-difluoro- 2-( 3-methyl-4H l ,2,4-triazol-4-yl )benzophenone was heated with paraformaldehyde in xylene to give 2',6'- difluoro-2-[ 3-( hydroxymethyl )5-methyl-4H-l ,2,4- triazol-4-yl ]benzophenone.

PREPARATION 30 2'6'-difluoro-2-[ 3-( bromomethyl )5-methyl-4H- l ,2,4- triazol-4'yl benzophenone In the manner given in Preparation 22, 2,6'-difluoro- 2-[ 3-( hydroxymethyl )-5-methyl-4H-l ,2,4-triazol-4- yllbenzophenone in chloroform was treated with phosgive 2',6'-difluoro-2-[3- 4H- 1 ,2,4-triazoI-4- phorus tribromide to (bromomethyl )-5-methylyl lbenzophenone.

PREPARATION 3 l 2' 6'-difluoro-2-[ 3-[(dimethylamino)methyl1-5- methyl-4H- l ,2,4-triazol-4-yl ]benzophenone In the manner given in Preparation 23, 2',6'-difluor0- 2-[ 3-( bromomethyl )-5-methyl-4H- l ,2,4-triazol-4- yl]benzophenone in tetrahydrofuran was treated with dimethylamine to give 2 ',6'-difluoro-2-[ 3- [(dimethylamino )methyl]-5-methyl-4H- l ,2,4-triazol- 4-yllbenzophenone.

Other starting compounds can be prepared, as shown in the foregoing examples, such as:

EXAMPLE I 5-chloro-2-( 3-methyl-4H-l ,2,4-triazol-4-yl) benzhydrol and its hydrate 5-chloro-2-( 3-methyl-4H-l ,2,4-triazol'4- yl)bcnzophenone (0.298 g., 0.00l mole) was added to a stirred, ice-cold suspension of sodium borohydride (300 mg.) in ethanol 10 ml. and the resulting mixture was stirred under nitrogen at ambient temperature for IS hours and concentrated in vacuo. The residue was suspended in water and extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated. Crystallization of this residue from ethanolethyl acetate gave: 0.272 g. of 5-chloro-2-( 3-methyl-4H-l ,2,4-triazol-4- yl)benzhydrol hydrate of melting point l59.5-l69 C.

Anal. calcd. for C ,-H ClN;,0.l/2H O: C, 62.24; H, 4.90; CI, ll.48. Found: C, 62.l4; H. 4.78; Cl, ll.70; H O, l.84.

The pure anhydrous benzhydrol was obtained by heating the hydrate to in vacuo for 72 hours.

EXAMPLE 2 5-chloro-2-[5-methyl- 3-( pyrrolidinomethyl )-4H- l ,2,4- triazol-4-yllbenzhydrol, isomers A and B To a 10 ml. flask with a magnetic stirrer bar was added 0.3805 g. (2.00 mmol) of 5-chloro-2-[5-methyl- 3(pyrrolidinomethyl)-4H-1,2,4-triazol-4- yljbenzophenone, and- 1.0 ml. of absolute ethanol. The mixture was cooled to 0 in an ice bath. Solid sodium borohydride (0.375 g., 1.00 mmol) was added in one portion and the mixture was stirred for 5 minutes at 0 C. The ice bath was removed and the stirring was continued. Within an additional l0 minutes all undissolved material disappeared. The mixture was stirred overnight. The reaction was worked up by cautiously adding hydrochloric acid to the mixture until gas evolution ceased. The mixture was then treated with 5% sodium hydroxide (the pH of the solution was made 9) and extracted with chloroform. Removal of chloroform left a diglyme solution. To the hot solution was added ether and hexane. Crystallization yielded I50 mg. of a white solid. Recrystallization (twice) afforded 50 mg. of white needles of 5-chloro-2-[ S-methyl- 3- (pyrrolidinomethyl )-4H- 1 ,2.4-triazol-4-yl ]benzhydrol isomer A of melting point 204205 C. [TLC (silica gel, l% methanol/chloroform) revealed that this solid corresponded to the slower moving epimer of R,().26. 1

Anal. calcd. for C H ClN O: C, 65.87; H, 6.06; N, 14.64; Cl, 9.26 Found: C. 65.78; H, 6.09; N, 14.66; Cl, 9.46.

The mother liquors from the crystallizations were re combined and dissolved in 3 ml. of diglyme. To be certain that all boron salts had been decomposed, the solu tion of mother liquors was refluxed for 3 hours with 3.0 ml. of methanol and 0.5 ml. of propionic acid. It was quenched in aq. '71 sodium hydroxide and worked up as described above. The material was chromatographed over g. of Silica Gel G using 60 ml. of chloroform (fractions A, B, C), I20 ml. of 171 methanol- 9971 chloroform (fractions D, E, F, G, and H) and 200 ml. of 571 methanol-95% chloroform. Fractions A to J contained no products. Fractions K and L contained the fast moving epimer of R; 0.45. Fraction M contained a small amount of a mixture of the two epimers, whereas Fractions N, O. P, O, and R contained only the epimer of R 026. These last fractions were combined and crystallized from ethyl acetate/hexane to give mg. of white needles of melting point 204206 C. Fractions K and L were triturated with ether to yield a white solid which was recrystallized from ethyl acetate/hexane to yield 70 mg. of prisms (isomer B) of melting point l83-l85 C. R UAS.

Anal. calcd. for C H CIN O C, 65.87; H, 6.06; N, l4.64. Found: C, 65.47; H, 6.07; N, 14.36.

EXAMPLE 3 5-chloro-2-[5-methyl-3-(morpholinomethyl )-4H- l.2,4-triazol-4yl]benzhydrol (A and B) In the manner given in Example 2, 5-chloro-2-[5- methyl-3-( morpholinomcthyl )-4H- l .2,4-triazol-4- yl ]benzophenone in an ethanol-diglyme suspension was treated with potassium borohydride to give both A and B 5-chloro-2-l 5-methyl-3-( morpholinomethyl )-4H- l,2,4-triazol 4-yl ]benzhydrol which could be separated by column chromatography and fractional crystallization with etherhexane into the two diastereomers A and B.

EXAMPLE 4 5-chloro-2-l5-methyl-3-{dimethylamino)methyl)-4H- l,2,4-triazol4-yl]benzhydrol (A and B) In the manner given in Example 2. 5chloro-2-[5- methyl-3-( (dimethylamino )methyl)-4H- l ,2,4-triazol- 4-yl]benzophenone in an ethanol-diglyme suspension was treated with sodium borohydride to give both A and B 5-chloro-2-[5-methyl-3- ((dimethylamino )methyl )-4H- l ,2,4-triazol-4- yl]benzhydrol which could be separated by column chromatography and fraction crystallization with etherhexane into the two diastereomers A and B.

EXAMPLE 5 2',5-dichloro-2-[5-methyl-3-(piperidinomethyl)-4H- l,2,4-triazol-4-yl]benzhydrol (A and B) In the manner given in Example 2, 2',5-dichloro-2- [5-methyl-3-( piperidinomethyl )-4H- l ,2,4-triazol-4-yl] benzophenone in an ethanol-diglyme suspension was treated with sodium borohydride to give both A and B 2 ,5-dichloro-2[ 5-methyl-3-( piperidinomethyl )-4H- l,2,4-triazol-4yl]benzhydrol which could be separated by column chromatography and fractional crystallization with ether-hexane into the two diastereomers A and B.

EXAMPLE 6 2',5-dichloro-2-[ 5-methyl-3-( pyrrolidinomethyl )-4H- 1,2,4-triazol-4-yl]benzhydrol (A and B) In the manner given in Example 2, 2',5-dichloro-2- [5-methyl-3-( pyrrolidinomethyl )-4H-l ,2,4-triazol-4- yl ]-benzophenone in an ethanol-diglyme suspension was treated with potassium borohydride to give both A and B 2',5-dichloro-2-[5-methyl-3- (pyrrolidinomethyl)-4H-1,2,4triazol-4-yl]benzhydrol which could be separated by column chromatography and fractional crystallization with ether-hexane into the two diastereomers A and B.

EXAMPLE 7 2' .6 '-Difluoro-5-chloro-2-[ 5-methyl-3- (morpholinomethyl )-4H- 1 ,2,4-triazol-4-yl ]benzhydrol (A and B) In the manner given in Example 2, 2',6'-difluoro-5- chloro-2-[5-methyI-3-( morpholinomethyl )-4H-l ,2,4- triazol-4-yl1benzophenone in an ethanol-diglyme suspension was treated with sodium borohydride to give both A and B 2',6-difluoro-5-chloro-2-[S-methyl-3- (morpholinomethyl )-4H- l ,2 ,4-triazol-4-yl ]benzhydrol which could be separated by column chromatography and fraction crystallization with ether-hexane into the two diastereomers A and B.

EXAMPLE 8 2',5-[dichloro-2-[ S-methyl-3-dimethylamino) methyI]-4Hl ,2,4-triazoI-4-yl]benzhydrol (A and B).

In the manner given in Example 2, 2',5-diehloro 2- {5-methyl-3-[ (dimethylamino )methyl -4H- l ,2,4- triazoI-4-yl1benzophenone in an ethanohdiglyme suspension was treated with potassium borohydride to give both A and B 2' 5-dichloro- 2-[ S-methyl- [(dipropylamino )methyl -3-4H- I ,2 ,4]-benzhydrol which could be separated by column chromatography and fractional crystallization with etherhexane into the two diastereomers A and B.

EXAMPLE 9 5-chloro-2-[3((diethylamino)methyl)-5-methyl4H- l,2,4-triazol-4-yl]benzhydrol (A and B) In the manner given in Example 2, 5-chloro-2-[3- ((diethylamino )methyl )-5-methyl-4H- l ,2 ,4-triazol-4- yl ]benzophenone in an ethanol-diglyme suspension was treated with sodium borohydride to give both A and B 5-chloro-2-[ 3-( (diethylamino)methyl )-S-methyl-4H- 1,2,4-triazol-4-yl ]benzhydrol which could be separated by column chromatography and fractional crystallization with ether-hexane into the two diastereomers A and 8.

EXAMPLE l 2',5-Dichloro-2-[5-methyl-3-(morpholinomethyl)-4H- l,2,4-triazol-4-yllbenzhydrol (A and B) In the manner given in Example 2. 2,5-dichloro-2- [S-methyl- 3-( morpholinomethyl )-4H- 1 ,2.4-triazol-4- yl ]bcnzophenone in an ethanoldiglyme suspension was treated with potassium borohydride to give both A and B 2'.5-dichloro-2-[ -methyl-3-( morpholinomethyl 4H-1,2,4-triazol-4-yl]benzhydrol which could be separated by column chromatography and fractional crystallization with etherhexane into the two diastereomers A and B.

EXAMPLE I l 2'.6-difluoro-5-chloro-2-[5-methyl-3- (pyrolidinomethyl )-4H- I ,2,4-triazol-4-yl]benzhydrol (A and B) In the manner given in Example 2, 2',6-difluoro-5- chloro-2-l 5-methyl-3-( pyrrolidinomethyl )-4H-1 .2,4- triazol-4-yllbenzophenone in an ethanol-diglyme suspension was treated with potassium borohydride to give both A and B 2,6'-difluoro-5-chloro-2-[5-methyl-3- (pyrrolidinomethyl )-4H-l .2,4-triazol-4-yllbenzhydrol which could be separated by column chromatography and fractional crystallization with ether-hexane into the two diastereomers A and B.

EXAMPLE [2 5-chloro-2 ',6'-difl uoro-2-[ 3-( piperidinomethyl )-5- methyl-4H-l,2.4-triazol-4-yllbenzhydrol (A and B) EXAMPLE [3 5-chloro-26'-difluoro-2-[5-methyl-3- [(dimethylamino)-methyl ]-4H- l ,2,4-triazol-4- yl]benzhydrol (A and B).

In the manner given in Example 2, 5-chloro-2'6'- difluoro-2-[5-methyl-3-[ dimethylamino )methyl]-4H- l,2.4triazol-4-yljbcnzophenone in an ethanol-diglyme suspension was treated with sodium borohydride to give both A and B 5-chloro-2',6'-difluoro-2-[S-methyl- 3-[ dimethylamino )-methyl ]-4H- 1 ,24-triazol-4 yl]benzhydrol which could be separated by column chromatography and fractional crystallization with ether-hexane into the two diastereomers A and B.

EXAMPLE l4 4-[ 2-Benzoyl-4-chlorophenyl ]-5-methyl-4H- l ,2,4- triazole-3-carboxaldehyde B-(O-acetyloxime) 4-( 2Benzoyl-4-chlorophenyl )-5-methyl-4H-l 2,4- triazole3-carboxaldehyde 3-oxime (2. [0 g.) was added to an ice cold solution of acetic anhydride (6 ml.) in pyridine (30 ml.) and the resulting mixture was stirred at ambient temperature, under nitrogen for IS hours and then poured into ice water. The solid was collected by filtration, washed with water, dried and crystallized from chloroform-ethanol to give 2.05 g. of 4-( 2 benzoyl-4-chlorophenyl)-5-methyl-4H-1 ,2,4-triazole- 3-carboxaldehyde 3-(O-acetyloxime) of melting point 17 l l 73 C. The analytical sample had a melting point of ll7l C.

Anal. calcd. for C H ClN O C, 59.45; H, 4.20; Cl, 9.24; N, 14.60. Found: C, 59.23; H. 3.92; C], 9.47; N,

In the manner given in Example l4 the acetates and propionates of other 4-( Z-benzoylphenyl )-S substituted 4H-l,2,4-triazole-3-carb0xaldehyde 3- oximes can be obtained by reacting a free oxime of formula III with acetic or propionic aldehyde. Representative compounds thus obtained include:

4-[ 2-( o-chlorobenzyl )-4-chlorophenyl -5-methyl-4H- 1,2,4-triazole-3-carboxaldehydc 3-O-acetyloxime; 4-[ 2-( 2,6-difluorobenzoyl )-4-chlorophenyl ]-5-methyl- 4H- .2,4-triazole-3-carboxaldehyde 3-O- propionyloxime and the like.

EXAMPLE l5 5-Chloro-2-[ 3-( aminomethyl )-5-methyl-4H- l ,2,4- triazol-4-yl]benzhydrol A lM solution of borane in tetrahydrofuran (68 ml.) was added to a stirred, ice cold solution of 4-(2- benzoyl-4-chlorophenyl )-5-methyl-4H-l ,2,4-triazolc- 3-carboxaldehyde-3-(0-acetyloxime) (4.34 g., 0.0l [3 mole) in ml. and the resulting solution was stirred. in the ice bath, under nitrogen. for 2 hours and for H5 hours at ambient temperature. This solution was cooled in an ice bath, treated with 6N hydrochloric acid [0.2 ml.) and concentrated in vacuo. A solution of the residue in methanol was again concentrated in vacuo. The reside was suspended in a mixture of water and ether and stirred for about 1 hour. The liquid was decanted from a gum. and the ether layer was extracted with dilute hydrochloric acid and water. The aqueous layer was combined with the aqueous extracts and gum, made alkaline with sodium hydroxide, and extracted with chloroform. The extract was washed with brine, dried over anhydrous potassium carbonate and concentrated. The residue was crystallized from methanolethyl acetate to give: 0.72 g. of 5-chloro-2-[3- (aminomethyl )-5-methyl-4H- l ,2,4-triazole-4- yl]benzhydrol as a mixture of diastereomers of melting point of 2092l2 C, and 0.77 g. of melting point 200206 C. The analytical sample had a melting point of 2l82l9 C.

Anal. calcd. for C H, ClN O: C, 62.10; H, 5.21; Cl, 10.78; N, 17.04. Found: C. 6L86; H. 5.15; Cl, lO.80; N, 16.99.

EXAMPLE l6 2',5-dichloro-2-[ 3-( aminomethyl )-5-methyl-4H-l ,2,4- triazol-4-yllbenzhydrol In the manner givenin Example l5, a solution of borane in tetrahydrofuran was added to a cold solution of 4-[2-(o-chlorobenzoyl )-4-chlorophenyl ]-5-methyl-4H- l ,2,4-triazole-3-carboxaldehyde-3-0-acetyloxime to give 2',5-dichloro-2-[3-(aminomethyl)-5-methyl-4H- l ,2.4-triazol-4-yl ]benzhydrol.

EXAMPLE l7 In the manner given to Example 15, a solution of borane in tetrahydrofuran was added to a cold solution of 4-[ 2-( l-difluorohenzoyl )-4-chlorophcnyl 1-5- methyllH-l .2.4-triazole-3-carboxaldehydc 3( propionyloxime) to give 5-chloro2'.6'-difluoro-2-{ 3- (aminomethyl i-S-methyllH- l 2,4-triazol-4- yl]henzhydr0l EXAMPLE l8 in the manner given in Example 15. a solution of horane in tetrahydrofuran was added to a cold solution of 4-[ 2% o-fl uorohenzoyl J-S-chlorophenyl l-5-mcthyl-4H- l 2,4-triazole-3-carhoxaldehyde 3(U-acet vloxime) to give i-chloro-Z '-fl uoro-2-[ 3-( aminomethyl J-5-meth vl- 4H- 1 ZA-triazolA-yl jbenzhydrol.

Treatment of the compounds of formula VI with a pharmacologicall acceptable acid such as hydrochlo ric. hylrohromic. phosphoric. sulfuric, acetic propi 3. 2 .5-Dichl0r0-3 l 5 -methyl-3-[ Ldimethylamino) methyllAH-l.2.4-tria1ol-4-yllhenzhydr0l. 

1. 5-CHLORO-2-(5-METHYL-3-((DIMETHYLAMINO)METHYL-4H1,2,4-TRIAZOL -4YL)BENZHYDROL.
 2. 5-Chloro-2'',6''-difluoro-(5-methyl-3-(dimethylamino)-methyl)-4H-1,2,4-triazol-4-yl)benzhydrol.
 3. 2'',5-Dichloro-2-(5-methyl-3-((dimethylamino)methyl)-4H-1,2,4-triazol-4 -yl)benzhydrol.
 4. 2'',5-Dichloro-2-(5-methyl-3-(aminomethyl)-4H-1,2,4-triazol-4-yl)benzhydrol. 